Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*...Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*G93A transgenic(ALS mouse model) and wide-type mice.This involved intraperitoneal injections of either granisetron,piboserod,or ritanserin,which inhibit the 5-HT3,5-HT4,and 5-HT2 receptors,respectively.The transgenic mice were found to have fewer5-HT-positive cells in the spinal cord compared with wide-type mice.We found that the administration of granisetron reduced the body weight of the transgenic mice,while piboserod and ritanserin worsened the motor functioning,as assessed using a hanging wire test.However,none of the 5-HT receptor antagonists affected the disease progression.We analyzed the distribution and/or expression of TAR DNA binding protein 43(TDP-43) and superoxide dismutase 1 G93A(SOD1-G93A),which fo rm abnormal aggregates in ALS.We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists.In addition,the disease-related mislocalization of TD P-43 to the cytoplasm increased markedly for all three drugs.In ce rtain anatomical regions,the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons.These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells.5-HT co uld therefore be a potential therapeutic target for amyotrophic lateral sclerosis.展开更多
Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types...Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.展开更多
Objective To explore the protective effects and mechanism of Zuogui Jiangtang Jieyu Formula(左归降糖解郁方,ZGJTJYF)on hippocampal neurons in rats of diabetes complicated with depression(DD)via the TRP/KYN metabolic pa...Objective To explore the protective effects and mechanism of Zuogui Jiangtang Jieyu Formula(左归降糖解郁方,ZGJTJYF)on hippocampal neurons in rats of diabetes complicated with depression(DD)via the TRP/KYN metabolic pathway.Methods(i)In vivo experiments:60 specified pathogen free(SPF)grade male Sprague-Dawley(SD)rats were randomly divided into six groups with 10 rats in each groups:control,DD model,positive(1.8 mg/kg fluoxetine+0.18 g/kg metformin),high-dose ZGJTJYF(ZGJTJYFH,40.500 g/kg ZGJTJYF),middle-dose ZGJTJYF(ZGJTJYF-M,20.250 g/kg ZGJTJYF),and lowdose ZGJTJYF(ZGJTJYF-L,10.125 g/kg ZGJTJYF)groups.Except for the control group,other groups were established DD model by high-fat emulsion intake with single tail vein streptozotocin(STZ)and four weeks of chronic unpredictable mild stress(CUMS).All drug administration groups were treated by gavage during CUMS modeling,and the control and model groups were given equal amount of distilled water.After four weeks,the serum levels of blood glucose and glycosylated hemoglobin were measured to determine the hypoglycemic effect of ZGJTJYF.Moreover,the open field test and Morris water maze test were performed to evaluate the antidepressant effect of ZGJTJYF.Changes in 5-hydroxytryptamine(5-HT)level were detected via high-performance liquid chromatography with electrochemical detection(HPLC-ECD);the levels of tryptophan(TRP),kynurenine(KYN),and indoleamine 2,3-dioxygenase(IDO)in the hippocampus were detected using enzyme-linked immunosorbent assay(ELISA);the protein expression levels of synaptophysin(SYN)and postsynaptic density material-95(PSD-95)were detected via immunohistochemistry(IHC);and the protein expression levels of N-methyl-D-aspartate receptor(NR)2 A and NR2 B were detected using Western blot.(ii)In vitro experiments:five SPF grade SD pregnant rats(E16–18)were used to obtain primary hippocampal neurons(Ne),six SD new-born rats were used to collected primary astrocytes(As)and microglia(MG),and to establish a Ne-As-MG co-culture system.All co-culture systems were divided into six groups:control(PBS),model[150 mmol/L glucose+200μmol/L corticosterone(G&P)+PBS],blank(G&P+blank serum),positive(G&P+positive drug-containing serum),ZGJTJYF(G&P+ZGJTJYF serum),and 1-methyl-D-tryptophan(1-MT,IDO inhibitor)(G&P+1-MT)groups.After 18 h of intervention by corresponding treatment,immunofluorescence was used to analyze the protein expression levels of SYN,PSD-95,NR2 A,and NR2 B;ELISA was performed to measure the levels of interleukin(IL)-1β,IL-6,tumor necrosis factor(TNF)-α,and TRP/KYN metabolic pathway-related factors[TRP,KYN,kynurenine acid(KYNA),quinolinic acid(QUIN)].Results(i)In vivo experimental results showed that ZGJTJYF-M and ZGJTJYF-L significantly improved the elevated blood glucose state of DD rats(P<0.01 and P<0.05,respectively);ZGJTJYF-H,ZGJTJYF-M,and ZGJTJYF-L increased their autonomous activity,learning,and memory ability(P<0.01,P<0.01,and P<0.05,respectively).Moreover,the levels of 5-HT and TRP were significantly increased(P<0.01),and the levels of KYN and IDO were significantly decreased in the hippocampus(P<0.01)of rats after ZGJTJYF-M treatment.The protein expression levels of SYN and PSD-95 were significantly upregulated in hippocampal neurons(P<0.01),while the abnormal activation of NR2A and NR2B was markedly inhibited in hippocampus(P<0.05)of rats after ZGJTJYF-M treatment.(ii)In vitro experimental results showed that ZGJTJYF-containing serum significantly increased the protein expression levels of SYN and PSD-95 in hippocampal neurons(P<0.01),decreased the levels of IL-1β(P<0.01),IL-6(P<0.05),TNF-α(P<0.01),IDO(P<0.05),KYN(P<0.05),and QUIN(P<0.01),and increased the levels of TRP and KYNA(P<0.01)in the simulated DD state.ZGJTJYF also had an significantly inhibitory effect on the abnormal activation of NR2A and NR2B in neurons(P<0.05)in a stimulated DD state.Conclusion ZGJTJYF can effectively improve 5-HT deficiency in the hippocampus of rats by inhibiting IDO expression and regulating the TRP/KYN metabolic pathway,and it has a favorable protective effect on hippocampal neuron injury caused by DD.Therefore,ZGJTJYF is an effective potential therapeutic drug for the prevention and treatment of DD.展开更多
Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is unknown whether the 5-hydroxytr...Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is unknown whether the 5-hydroxytryptamine 2A receptor（5-HT2AR） is involved in the effects of prenatal alcohol exposure. In the present study, pregnant female rats received drinking water containing alcohol at concentrations of 0%, 1%, 2%, 4%, 8% or 10%（v/v） throughout the gestation period. Slices of the medulla from 2-day-old neonatal rats were obtained to record respiratory rhythmical discharge activity. 5-HT2 AR protein and m RNA levels in the pre-B？tzinger complex of the respiratory center were measured by western blot analysis and quantitative RT-PCR, respectively. Compared with the 0% alcohol group, respiratory rhythmical discharge activity in medullary slices in the 4%, 8% and 10% alcohol groups was decreased, and the reduction was greatest in the 8% alcohol group. Respiratory rhythmical discharge activity in the 10% alcohol group was irregular. Thus, 8% was the most effective alcohol concentration at attenuating respiratory rhythmical discharge activity. These findings suggest that prenatal alcohol exposure attenuates respiratory rhythmical discharge activity in neonatal rats by downregulating 5-HT2 AR protein and m RNA levels.展开更多
Many research works through out the world show that the preoptic area(POA) is a region concerned with analgesia. Electric stimulation to this region could enhance markedly pain threshold and exert an analgesic effect....Many research works through out the world show that the preoptic area(POA) is a region concerned with analgesia. Electric stimulation to this region could enhance markedly pain threshold and exert an analgesic effect. Central 5-hydroxytryptamine (5-HT) plays an important role in pain mediation. Acupuncture could accelerate the synthe-展开更多
基金supported by the National Natural Science Foundation of China,Nos.30560042,81160161,8136019882160255+2 种基金Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021Jiangxi Provincial Department of Science and Technology,Nos.20142BBG70062,20171 BAB215022,20192BAB205043Health and Family Planning Commission of Jiangxi Province,No.20181019 (all to RSX)。
文摘Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis(ALS) is closely linked to 5-hydroxytryptamine(5-HT).To investigate this further,we administered 5-HT receptor antagonists to SOD1*G93A transgenic(ALS mouse model) and wide-type mice.This involved intraperitoneal injections of either granisetron,piboserod,or ritanserin,which inhibit the 5-HT3,5-HT4,and 5-HT2 receptors,respectively.The transgenic mice were found to have fewer5-HT-positive cells in the spinal cord compared with wide-type mice.We found that the administration of granisetron reduced the body weight of the transgenic mice,while piboserod and ritanserin worsened the motor functioning,as assessed using a hanging wire test.However,none of the 5-HT receptor antagonists affected the disease progression.We analyzed the distribution and/or expression of TAR DNA binding protein 43(TDP-43) and superoxide dismutase 1 G93A(SOD1-G93A),which fo rm abnormal aggregates in ALS.We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists.In addition,the disease-related mislocalization of TD P-43 to the cytoplasm increased markedly for all three drugs.In ce rtain anatomical regions,the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons.These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells.5-HT co uld therefore be a potential therapeutic target for amyotrophic lateral sclerosis.
基金supported by the STI 2030—Major Projects 2021ZD0204000,No.2021ZD0204003 (to XZ)the National Natural Science Foundation of China,Nos.32170973 (to XZ),32071018 (to ZH)。
文摘Dysregulation of neurotransmitter metabolism in the central nervous system contributes to mood disorders such as depression, anxiety, and post–traumatic stress disorder. Monoamines and amino acids are important types of neurotransmitters. Our previous results have shown that disco-interacting protein 2 homolog A(Dip2a) knockout mice exhibit brain development disorders and abnormal amino acid metabolism in serum. This suggests that DIP2A is involved in the metabolism of amino acid–associated neurotransmitters. Therefore, we performed targeted neurotransmitter metabolomics analysis and found that Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex. In addition, acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala. Additionally, Dip2a was abundantly expressed in excitatory neurons of the basolateral amygdala, and deletion of Dip2a in these neurons resulted in hopelessness-like behavior in the tail suspension test. Altogether, these findings demonstrate that DIP2A in the basolateral amygdala may be involved in the regulation of stress susceptibility. This provides critical evidence implicating a role of DIP2A in affective disorders.
基金National Natural Science Foundation of China(81874464and 82104793)the Scientific Research Project of Education Department of Hunan Province(19K066)。
文摘Objective To explore the protective effects and mechanism of Zuogui Jiangtang Jieyu Formula(左归降糖解郁方,ZGJTJYF)on hippocampal neurons in rats of diabetes complicated with depression(DD)via the TRP/KYN metabolic pathway.Methods(i)In vivo experiments:60 specified pathogen free(SPF)grade male Sprague-Dawley(SD)rats were randomly divided into six groups with 10 rats in each groups:control,DD model,positive(1.8 mg/kg fluoxetine+0.18 g/kg metformin),high-dose ZGJTJYF(ZGJTJYFH,40.500 g/kg ZGJTJYF),middle-dose ZGJTJYF(ZGJTJYF-M,20.250 g/kg ZGJTJYF),and lowdose ZGJTJYF(ZGJTJYF-L,10.125 g/kg ZGJTJYF)groups.Except for the control group,other groups were established DD model by high-fat emulsion intake with single tail vein streptozotocin(STZ)and four weeks of chronic unpredictable mild stress(CUMS).All drug administration groups were treated by gavage during CUMS modeling,and the control and model groups were given equal amount of distilled water.After four weeks,the serum levels of blood glucose and glycosylated hemoglobin were measured to determine the hypoglycemic effect of ZGJTJYF.Moreover,the open field test and Morris water maze test were performed to evaluate the antidepressant effect of ZGJTJYF.Changes in 5-hydroxytryptamine(5-HT)level were detected via high-performance liquid chromatography with electrochemical detection(HPLC-ECD);the levels of tryptophan(TRP),kynurenine(KYN),and indoleamine 2,3-dioxygenase(IDO)in the hippocampus were detected using enzyme-linked immunosorbent assay(ELISA);the protein expression levels of synaptophysin(SYN)and postsynaptic density material-95(PSD-95)were detected via immunohistochemistry(IHC);and the protein expression levels of N-methyl-D-aspartate receptor(NR)2 A and NR2 B were detected using Western blot.(ii)In vitro experiments:five SPF grade SD pregnant rats(E16–18)were used to obtain primary hippocampal neurons(Ne),six SD new-born rats were used to collected primary astrocytes(As)and microglia(MG),and to establish a Ne-As-MG co-culture system.All co-culture systems were divided into six groups:control(PBS),model[150 mmol/L glucose+200μmol/L corticosterone(G&P)+PBS],blank(G&P+blank serum),positive(G&P+positive drug-containing serum),ZGJTJYF(G&P+ZGJTJYF serum),and 1-methyl-D-tryptophan(1-MT,IDO inhibitor)(G&P+1-MT)groups.After 18 h of intervention by corresponding treatment,immunofluorescence was used to analyze the protein expression levels of SYN,PSD-95,NR2 A,and NR2 B;ELISA was performed to measure the levels of interleukin(IL)-1β,IL-6,tumor necrosis factor(TNF)-α,and TRP/KYN metabolic pathway-related factors[TRP,KYN,kynurenine acid(KYNA),quinolinic acid(QUIN)].Results(i)In vivo experimental results showed that ZGJTJYF-M and ZGJTJYF-L significantly improved the elevated blood glucose state of DD rats(P<0.01 and P<0.05,respectively);ZGJTJYF-H,ZGJTJYF-M,and ZGJTJYF-L increased their autonomous activity,learning,and memory ability(P<0.01,P<0.01,and P<0.05,respectively).Moreover,the levels of 5-HT and TRP were significantly increased(P<0.01),and the levels of KYN and IDO were significantly decreased in the hippocampus(P<0.01)of rats after ZGJTJYF-M treatment.The protein expression levels of SYN and PSD-95 were significantly upregulated in hippocampal neurons(P<0.01),while the abnormal activation of NR2A and NR2B was markedly inhibited in hippocampus(P<0.05)of rats after ZGJTJYF-M treatment.(ii)In vitro experimental results showed that ZGJTJYF-containing serum significantly increased the protein expression levels of SYN and PSD-95 in hippocampal neurons(P<0.01),decreased the levels of IL-1β(P<0.01),IL-6(P<0.05),TNF-α(P<0.01),IDO(P<0.05),KYN(P<0.05),and QUIN(P<0.01),and increased the levels of TRP and KYNA(P<0.01)in the simulated DD state.ZGJTJYF also had an significantly inhibitory effect on the abnormal activation of NR2A and NR2B in neurons(P<0.05)in a stimulated DD state.Conclusion ZGJTJYF can effectively improve 5-HT deficiency in the hippocampus of rats by inhibiting IDO expression and regulating the TRP/KYN metabolic pathway,and it has a favorable protective effect on hippocampal neuron injury caused by DD.Therefore,ZGJTJYF is an effective potential therapeutic drug for the prevention and treatment of DD.
基金the Natural Science Foundation of Henan Province in China,No.102102310156the Foundation of Xinxiang Technology Bureau in China,No.ZG14004
文摘Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is unknown whether the 5-hydroxytryptamine 2A receptor（5-HT2AR） is involved in the effects of prenatal alcohol exposure. In the present study, pregnant female rats received drinking water containing alcohol at concentrations of 0%, 1%, 2%, 4%, 8% or 10%（v/v） throughout the gestation period. Slices of the medulla from 2-day-old neonatal rats were obtained to record respiratory rhythmical discharge activity. 5-HT2 AR protein and m RNA levels in the pre-B？tzinger complex of the respiratory center were measured by western blot analysis and quantitative RT-PCR, respectively. Compared with the 0% alcohol group, respiratory rhythmical discharge activity in medullary slices in the 4%, 8% and 10% alcohol groups was decreased, and the reduction was greatest in the 8% alcohol group. Respiratory rhythmical discharge activity in the 10% alcohol group was irregular. Thus, 8% was the most effective alcohol concentration at attenuating respiratory rhythmical discharge activity. These findings suggest that prenatal alcohol exposure attenuates respiratory rhythmical discharge activity in neonatal rats by downregulating 5-HT2 AR protein and m RNA levels.
文摘Many research works through out the world show that the preoptic area(POA) is a region concerned with analgesia. Electric stimulation to this region could enhance markedly pain threshold and exert an analgesic effect. Central 5-hydroxytryptamine (5-HT) plays an important role in pain mediation. Acupuncture could accelerate the synthe-
